A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors
Summary Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/...
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| Veröffentlicht in: | Investigational new drugs 2017-10, Vol.35 (5), p.576-588 |
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| creator | Infante, Jeffrey R. Cohen, Roger B. Kim, Kevin B. Burris, Howard A. Curt, Gregory Emeribe, Ugochi Clemett, Delyth Tomkinson, Helen K. LoRusso, Patricia M. |
| description | Summary
Background
Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors.
Methods
Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects.
Results
48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles.
Conclusions
MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.
Trial registration:
ClinicalTrials.gov
NCT00600496; registered 8 July 2009. |
| doi_str_mv | 10.1007/s10637-017-0459-7 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5613062</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1949611657</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-b6871851ae446ebf7c14e7c36af76e2cadac458ae321e612cb3b6ea2b3d631e23</originalsourceid><addsrcrecordid>eNp1kcFu1TAQRS0Eoo_CB7BBltiwCXhsx042SFXVlkqVWFDWluNM-lwl9sNOirrmx3GUUhUkFtYs7pnrmbmEvAX2ERjTnzIwJXTFoDxZt5V-RnZQa1ExJdVzsmOgdKXaVh-RVznfMsZEq-VLcsQbyWXTwo78OqGHvc1IL2kfM1aYnR3t7GOgeV76exoH-g3HZcLZB99RH6iLU-fDxvz0856epTFuakz0GqfsUxz9tOSVPhQQw5w31PZ3NjjsaS5ET-dliim_Ji8GO2Z881CPyffzs-vTL9XV14vL05OryknN5qpTjYamBotSKuwG7UCidkLZQSvkzvbWybqxKDigAu460Sm0vBO9EoBcHJPPm-9h6SbsXRkr2dEckp9sujfRevO3Evze3MQ7UysQTK0GHx4MUvyxYJ7N5LPDcbQB45INlJOyphFcF_T9P-htXFIo6xloZasAVL1SsFEuxZwTDo_DADNrxGaL2JSIzRqxWXvePd3iseNPpgXgG5CLFG4wPfn6v66_AYf9tQ8</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1949611657</pqid></control><display><type>article</type><title>A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Infante, Jeffrey R. ; Cohen, Roger B. ; Kim, Kevin B. ; Burris, Howard A. ; Curt, Gregory ; Emeribe, Ugochi ; Clemett, Delyth ; Tomkinson, Helen K. ; LoRusso, Patricia M.</creator><creatorcontrib>Infante, Jeffrey R. ; Cohen, Roger B. ; Kim, Kevin B. ; Burris, Howard A. ; Curt, Gregory ; Emeribe, Ugochi ; Clemett, Delyth ; Tomkinson, Helen K. ; LoRusso, Patricia M.</creatorcontrib><description>Summary
Background
Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors.
Methods
Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects.
Results
48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles.
Conclusions
MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.
Trial registration:
ClinicalTrials.gov
NCT00600496; registered 8 July 2009.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-017-0459-7</identifier><identifier>PMID: 28424891</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject><![CDATA[Allosteric properties ; Anticancer properties ; Antineoplastic Agents - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Antitumor agents ; Benzimidazoles - administration & dosage ; Constraining ; Diarrhea ; Dose-Response Relationship, Drug ; Drugs ; Erlotinib Hydrochloride - administration & dosage ; Exanthema ; Fatigue ; Female ; Humans ; Inhibitor drugs ; Male ; Maximum Tolerated Dose ; Medicine ; Medicine & Public Health ; Metabolic pathways ; Middle Aged ; Mucositis ; Nausea ; Neoplasms - drug therapy ; Neutropenia ; Oncology ; Patients ; Pharmacokinetics ; Pharmacology ; Pharmacology/Toxicology ; Phase I Studies ; Protein Kinase Inhibitors - administration & dosage ; Raf protein ; Safety ; Sirolimus - administration & dosage ; Sirolimus - analogs & derivatives ; Solid tumors ; Studies ; Targeted cancer therapy ; Toxicity ; Tumors]]></subject><ispartof>Investigational new drugs, 2017-10, Vol.35 (5), p.576-588</ispartof><rights>The Author(s) 2017</rights><rights>Investigational New Drugs is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-b6871851ae446ebf7c14e7c36af76e2cadac458ae321e612cb3b6ea2b3d631e23</citedby><cites>FETCH-LOGICAL-c470t-b6871851ae446ebf7c14e7c36af76e2cadac458ae321e612cb3b6ea2b3d631e23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-017-0459-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-017-0459-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28424891$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Infante, Jeffrey R.</creatorcontrib><creatorcontrib>Cohen, Roger B.</creatorcontrib><creatorcontrib>Kim, Kevin B.</creatorcontrib><creatorcontrib>Burris, Howard A.</creatorcontrib><creatorcontrib>Curt, Gregory</creatorcontrib><creatorcontrib>Emeribe, Ugochi</creatorcontrib><creatorcontrib>Clemett, Delyth</creatorcontrib><creatorcontrib>Tomkinson, Helen K.</creatorcontrib><creatorcontrib>LoRusso, Patricia M.</creatorcontrib><title>A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Background
Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors.
Methods
Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects.
Results
48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles.
Conclusions
MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.
Trial registration:
ClinicalTrials.gov
NCT00600496; registered 8 July 2009.</description><subject>Allosteric properties</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Antitumor agents</subject><subject>Benzimidazoles - administration & dosage</subject><subject>Constraining</subject><subject>Diarrhea</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drugs</subject><subject>Erlotinib Hydrochloride - administration & dosage</subject><subject>Exanthema</subject><subject>Fatigue</subject><subject>Female</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic pathways</subject><subject>Middle Aged</subject><subject>Mucositis</subject><subject>Nausea</subject><subject>Neoplasms - drug therapy</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Raf protein</subject><subject>Safety</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Solid tumors</subject><subject>Studies</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp1kcFu1TAQRS0Eoo_CB7BBltiwCXhsx042SFXVlkqVWFDWluNM-lwl9sNOirrmx3GUUhUkFtYs7pnrmbmEvAX2ERjTnzIwJXTFoDxZt5V-RnZQa1ExJdVzsmOgdKXaVh-RVznfMsZEq-VLcsQbyWXTwo78OqGHvc1IL2kfM1aYnR3t7GOgeV76exoH-g3HZcLZB99RH6iLU-fDxvz0856epTFuakz0GqfsUxz9tOSVPhQQw5w31PZ3NjjsaS5ET-dliim_Ji8GO2Z881CPyffzs-vTL9XV14vL05OryknN5qpTjYamBotSKuwG7UCidkLZQSvkzvbWybqxKDigAu460Sm0vBO9EoBcHJPPm-9h6SbsXRkr2dEckp9sujfRevO3Evze3MQ7UysQTK0GHx4MUvyxYJ7N5LPDcbQB45INlJOyphFcF_T9P-htXFIo6xloZasAVL1SsFEuxZwTDo_DADNrxGaL2JSIzRqxWXvePd3iseNPpgXgG5CLFG4wPfn6v66_AYf9tQ8</recordid><startdate>20171001</startdate><enddate>20171001</enddate><creator>Infante, Jeffrey R.</creator><creator>Cohen, Roger B.</creator><creator>Kim, Kevin B.</creator><creator>Burris, Howard A.</creator><creator>Curt, Gregory</creator><creator>Emeribe, Ugochi</creator><creator>Clemett, Delyth</creator><creator>Tomkinson, Helen K.</creator><creator>LoRusso, Patricia M.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7WY</scope><scope>7WZ</scope><scope>7X7</scope><scope>7XB</scope><scope>87Z</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8FL</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BEZIV</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FRNLG</scope><scope>FYUFA</scope><scope>F~G</scope><scope>GHDGH</scope><scope>K60</scope><scope>K6~</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>L.-</scope><scope>M0C</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQBIZ</scope><scope>PQBZA</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20171001</creationdate><title>A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors</title><author>Infante, Jeffrey R. ; Cohen, Roger B. ; Kim, Kevin B. ; Burris, Howard A. ; Curt, Gregory ; Emeribe, Ugochi ; Clemett, Delyth ; Tomkinson, Helen K. ; LoRusso, Patricia M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-b6871851ae446ebf7c14e7c36af76e2cadac458ae321e612cb3b6ea2b3d631e23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Allosteric properties</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Antitumor agents</topic><topic>Benzimidazoles - administration & dosage</topic><topic>Constraining</topic><topic>Diarrhea</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drugs</topic><topic>Erlotinib Hydrochloride - administration & dosage</topic><topic>Exanthema</topic><topic>Fatigue</topic><topic>Female</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic pathways</topic><topic>Middle Aged</topic><topic>Mucositis</topic><topic>Nausea</topic><topic>Neoplasms - drug therapy</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Raf protein</topic><topic>Safety</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Solid tumors</topic><topic>Studies</topic><topic>Targeted cancer therapy</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Infante, Jeffrey R.</creatorcontrib><creatorcontrib>Cohen, Roger B.</creatorcontrib><creatorcontrib>Kim, Kevin B.</creatorcontrib><creatorcontrib>Burris, Howard A.</creatorcontrib><creatorcontrib>Curt, Gregory</creatorcontrib><creatorcontrib>Emeribe, Ugochi</creatorcontrib><creatorcontrib>Clemett, Delyth</creatorcontrib><creatorcontrib>Tomkinson, Helen K.</creatorcontrib><creatorcontrib>LoRusso, Patricia M.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>ABI/INFORM Collection</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Global (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Global</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Business</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Infante, Jeffrey R.</au><au>Cohen, Roger B.</au><au>Kim, Kevin B.</au><au>Burris, Howard A.</au><au>Curt, Gregory</au><au>Emeribe, Ugochi</au><au>Clemett, Delyth</au><au>Tomkinson, Helen K.</au><au>LoRusso, Patricia M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2017-10-01</date><risdate>2017</risdate><volume>35</volume><issue>5</issue><spage>576</spage><epage>588</epage><pages>576-588</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Background
Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors.
Methods
Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects.
Results
48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles.
Conclusions
MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.
Trial registration:
ClinicalTrials.gov
NCT00600496; registered 8 July 2009.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>28424891</pmid><doi>10.1007/s10637-017-0459-7</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Investigational new drugs, 2017-10, Vol.35 (5), p.576-588 |
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| subjects | Allosteric properties Anticancer properties Antineoplastic Agents - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Antitumor agents Benzimidazoles - administration & dosage Constraining Diarrhea Dose-Response Relationship, Drug Drugs Erlotinib Hydrochloride - administration & dosage Exanthema Fatigue Female Humans Inhibitor drugs Male Maximum Tolerated Dose Medicine Medicine & Public Health Metabolic pathways Middle Aged Mucositis Nausea Neoplasms - drug therapy Neutropenia Oncology Patients Pharmacokinetics Pharmacology Pharmacology/Toxicology Phase I Studies Protein Kinase Inhibitors - administration & dosage Raf protein Safety Sirolimus - administration & dosage Sirolimus - analogs & derivatives Solid tumors Studies Targeted cancer therapy Toxicity Tumors |
| title | A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors |
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